Highly active antiretroviral therapy (HAART) can consistently reduce HIV viremia to below the limit of detection of clinical assays. However, virus persists in a latent form in resting memory CD4* T cells. Low levels of free virus particles are detected in plasma of patients on HAART;this residual viremia (RV) may represent ongoing cycles of viral replication not completely blocked by HAART or release of virus from latently infected cells that are activated. Release of virus from other stable reservoirs probably contributes to RV. We have shown in our SIV HAART Model that SIV persists in the central nervous system (CNS). Eradication of the infection will likely require HAART regimens that completely block new infection of susceptible cells. In addition, it will be necessary to identify all of the stable reservoirs where non-replicating forms of the virus persist in order to eliminate all reservoirs. Novel approaches for reducing or purging latent reservoirs have the potential for adverse effects so that testing of therapeutic approaches should initially be done in an animal model that recapitulates the latent viral reservoirs in HIV. Our SIV HAART Model mirrors the virologic state of patients on HAART, establishes latent infection in resting macaque CDA^ T cells, with frequencies of latently infected cells in blood, lymphoid organs and tissues of infected macaques very similar to HIV-1-infected humans. Despite the control of HIV replication and the decreased incidence of AIDS due to HAART, studies report that mild/moderate cognitive impairment occurs in up to 50 % of those on long term HAART. Further, it is not clear whether early versus delayed initiation of HAART impacts the CNS or development of cognitive impairment, the level of viral latency, residual viremia, or preservation of innate and adaptive immune responses. Our SIV HAART model provides a rigorous model to examine these issues as well as to test novel therapy to reduce or purge latent reservoirs in the CNS and other tissues. In the proposed studies, we will carry out critical experiments to characterize all viral reservoirs, particularly in CNS, PNS and progenitor cells in bone marrow. In addition, we will use this model to explore anatomical and cellular reservoirs in which virus reactivates during antiretroviral therapy, including those that cannot be readily studied in humans. We will also test eradication strategies designed to eliminate these reservoirs.